A Fatal Case of Pseudomonas aeruginosa Community-Acquired Pneumonia in an Immunocompetent Patient: Clinical and Molecular Characterization and Literature Review.

Rare cases of Pseudomonas aeruginosa community-acquired pneumonia (PA-CAP) were reported in non-immunocompromised patients. We describe a case of Pseudomonas aeruginosa (PA) necrotizing cavitary CAP with a fatal outcome in a 53-year-old man previously infected with SARS-CoV-2, who was admitted for dyspnea, fever, cough, hemoptysis, acute respiratory failure and a right upper lobe opacification. Six hours after admission, despite effective antibiotic therapy, he experienced multi-organ failure and died. Autopsy confirmed necrotizing pneumonia with alveolar hemorrhage. Blood and bronchoalveolar lavage cultures were positive for PA serotype O:9 belonging to ST1184. The strain shares the same virulence factor profile with reference genome PA01. With the aim to better investigate the clinical and molecular characteristics of PA-CAP, we considered the literature of the last 13 years concerning this topic. The prevalence of hospitalized PA-CAP is about 4% and has a mortality rate of 33-66%. Smoking, alcohol abuse and contaminated fluid exposure were the recognized risk factors; most cases presented the same symptoms described above and needed intensive care. Co-infection of PA-influenza A is described, which is possibly caused by influenza-inducing respiratory epithelial cell dysfunction: the same pathophysiological mechanism could be assumed with SARS-CoV-2 infection. Considering the high rate of fatal outcomes, additional studies are needed to identify sources of infections and new risk factors, along with genetic and immunological features. Current CAP guidelines should be revised in light of these results.

Persistent SARS-CoV-2 infection with multiple clinical relapses in two patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab.

PURPOSE: People with hematologic malignancies have a significantly higher risk of developing severe and protracted forms of SARS-CoV-2 infection compared to immunocompetent patients, regardless of vaccination status. RESULTS: We describe two cases of prolonged SARS-CoV-2 infection with multiple relapses of COVID-19 pneumonia in patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab. The aim is to highlight the complexity of SARS-CoV-2 infection in this fragile group of patients and the necessity of evidence-based strategies to treat them properly. CONCLUSIONS: Patients with hematological malignancies treated with bendamustine and anti-CD20 antibodies had a significant risk of prolonged and relapsing course of COVID-19. Specific preventive and therapeutic strategies should be developed for this group of patients.

Role of Selective Digestive Decontamination in the Prevention of Ventilator-Associated Pneumonia in COVID-19 Patients: A Pre-Post Observational Study.

The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator-associated pneumonia (VAP) in COVID-19 patients without changes in the microbiological pattern of antibiotic resistance. This observational pre-post study included adult patients requiring invasive mechanical ventilation (IMV) for severe respiratory failure related to SARS-CoV-2 admitted in three COVID-19 intensive care units (ICUs) in an Italian hospital from 22 February 2020 to 8 March 2022. Selective digestive decontamination (SDD) was introduced from the end of April 2021 in the structured protocol for VAP prevention. The SDD consisted of a tobramycin sulfate, colistin sulfate, and amphotericin B suspension applied in the patient's oropharynx and the stomach via a nasogastric tube. Three-hundred-and-forty-eight patients were included in the study. In the 86 patients (32.9%) who received SDD, the occurrence of VAP decreased by 7.7% (p = 0.192) compared to the patients who did not receive SDD. The onset time of VAP, the occurrence of multidrug-resistant microorganisms AP, the length of invasive mechanical ventilation, and hospital mortality were similar in the patients who received and who did not receive SDD. The multivariate analysis adjusted for confounders showed that the use of SDD reduces the occurrence of VAP (HR 0.536, CI 0.338-0.851; p = 0.017). Our pre-post observational study indicates that the use of SDD in a structured protocol for VAP prevention seems to reduce the occurrence of VAP without changes in the incidence of multidrug-resistant bacteria in COVID-19 patients.

Weekly Rapid Antigen Test Screening for COVID-19 in Patients on Hemodialysis.

BACKGROUND/AIM: COVID-19 is a concerning issue among in-center hemodialysis (HD) patients. To prevent COVID-19 diffusion in our HD facility, weekly rapid nasal antigen test screening was performed for all asymptomatic patients on chronic HD. This study aimed to assess the performance of weekly rapid antigen test in detecting SARS-CoV-2 infection among asymptomatic patients receiving HD. PATIENTS AND METHODS: A retrospective analysis was conducted in HD patients who underwent rapid antigen test screening from December 2021 to March 2022. The diagnosis of COVID-19 with rapid antigen test was always confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: During the observational period, 1,748 rapid antigen tests were performed in 220 HD patients. Mean age was 68.4±14.6 years. Fifteen (8.5%) patients resulted positive for SARS-CoV-2 infection using rapid antigen tests. The diagnosis was subsequently confirmed in 14 (93.3%) patients by RT-PCR. During the same period, 12 (5.4%) symptomatic patients, regularly screened with weekly rapid antigen test, resulted positive for SARS-CoV-2 infection using RT-PCR. Overall, weekly rapid antigen test screening identified 14 out of 26 (53.8%) COVID-19 cases and showed a positive predictive value of 93%. CONCLUSION: Weekly antigen test screening of asymptomatic patients on chronic HD detected around half of the COVID-19 cases in our population.

Ceftazidime/Avibactam in Ventilator-Associated Pneumonia Due to Difficult-to-Treat Non-Fermenter Gram-Negative Bacteria in COVID-19 Patients: A Case Series and Review of the Literature.

Ventilator-associated pneumonia (VAP) in critically ill patients with COVID-19 represents a very huge global threat due to a higher incidence rate compared to non-COVID-19 patients and almost 50% of the 30-day mortality rate. Pseudomonas aeruginosa was the first pathogen involved but uncommon non-fermenter gram-negative organisms such as Burkholderia cepacea and Stenotrophomonas maltophilia have emerged as other potential etiological causes. Against carbapenem-resistant gram-negative microorganisms, Ceftazidime/avibactam (CZA) is considered a first-line option, even more so in case of a ceftolozane/tazobactam resistance or shortage. The aim of this report was to describe our experience with CZA in a case series of COVID-19 patients hospitalized in the ICU with VAP due to difficult-to-treat (DTT) P. aeruginosa, Burkholderia cepacea, and Stenotrophomonas maltophilia and to compare it with data published in the literature. A total of 23 patients were treated from February 2020 to March 2022: 19/23 (82%) VAPs were caused by Pseudomonas spp. (16/19 DTT), 2 by Burkholderia cepacea, and 6 by Stenotrophomonas maltophilia; 12/23 (52.1%) were polymicrobial. Septic shock was diagnosed in 65.2% of the patients and VAP occurred after a median of 29 days from ICU admission. CZA was prescribed as a combination regimen in 86% of the cases, with either fosfomycin or inhaled amikacin or cotrimoxazole. Microbiological eradication was achieved in 52.3% of the cases and the 30-day overall mortality rate was 14/23 (60.8%). Despite the high mortality of critically ill COVID-19 patients, CZA, especially in combination therapy, could represent a valid treatment option for VAP due to DTT non-fermenter gram-negative bacteria, including uncommon pathogens such as Burkholderia cepacea and Stenotrophomonas maltophilia.

Long-Term Impact of the COVID-19 Pandemic on In-Hospital Antibiotic Consumption and Antibiotic Resistance: A Time Series Analysis (2015-2021).

The coronavirus disease 2019 (COVID-19)-pandemic-related overload of health systems has compromised the application of antimicrobial stewardship (AS) models and infection prevention and control (IPC) programs. We aimed to evaluate the impact of COVID-19 on antimicrobial consumption (AC) and antimicrobial resistance (AMR) in the University Hospital of Modena. A time series analysis with an autoregressive integrated moving average model was conducted from January 2015 to October 2021 to evaluate the AC in the whole hospital and the intensive care unit (ICU), the incidence density (ID) of bloodstream infections (BSIs) due to the main multidrug-resistant organisms, and of C. difficile infections (CDIs). After an initial peak during the COVID-19 period, a decrease in the trend of AC was observed, both at the hospital (CT: -1.104, p = 0.025) and ICU levels (CT: -4.47, p = 0.047), with no significant difference in the single classes. Among the Gram-negative isolates, we observed a significant increase only in the level of BSIs due to carbapenem-susceptible Pseudomonas aeruginosa (CL: 1.477, 95% CI 0.130 to 2.824, p = 0.032). Considering Gram-positive bacteria, an increase in the level of BSIs due to methicillin-resistant Staphylococcus aureus and in the trend of CDIs were observed, though they did not reach statistical significance (CL: 0.72, 95% CI -0.039 to 1.48, p = 0.062; CT: 1.43, 95% CI -0.002 to 2.863, p = 0.051; respectively). Our findings demonstrated that the increases in AMR and AC that appeared in the first COVID-19 wave may be later controlled by restoring IPC and AS programs to pre-epidemic levels. A coordinated healthcare effort is necessary to address the longer-term impact of COVID-19 on AC to avoid irreversible consequences on AMR.

Cytomegalovirus blood reactivation in COVID-19 critically ill patients: risk factors and impact on mortality.

PURPOSE: Cytomegalovirus (CMV) reactivation in immunocompetent critically ill patients is common and relates to a worsening outcome. In this large observational study, we evaluated the incidence and the risk factors associated with CMV reactivation and its effects on mortality in a large cohort of patients affected by coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). METHODS: Consecutive patients with confirmed SARS-CoV-2 infection and acute respiratory distress syndrome admitted to three ICUs from February 2020 to July 2021 were included. The patients were screened at ICU admission and once or twice per week for quantitative CMV-DNAemia in the blood. The risk factors associated with CMV blood reactivation and its association with mortality were estimated by adjusted Cox proportional hazards regression models. RESULTS: CMV blood reactivation was observed in 88 patients (20.4%) of the 431 patients studied. Simplified Acute Physiology Score (SAPS) II score (HR 1031, 95% CI 1010-1053, p = 0.006), platelet count (HR 0.0996, 95% CI 0.993-0.999, p = 0.004), invasive mechanical ventilation (HR 2611, 95% CI 1223-5571, p = 0.013) and secondary bacterial infection (HR 5041; 95% CI 2852-8911, p < 0.0001) during ICU stay were related to CMV reactivation. Hospital mortality was higher in patients with (67.0%) than in patients without (24.5%) CMV reactivation but the adjusted analysis did not confirm this association (HR 1141, 95% CI 0.757-1721, p = 0.528). CONCLUSION: The severity of illness and the occurrence of secondary bacterial infections were associated with an increased risk of CMV blood reactivation, which, however, does not seem to influence the outcome of COVID-19 ICU patients independently.

Long-Term Impact of the COVID-19 Pandemic on In-Hospital Antibiotic Consumption and Antibiotic Resistance: A Time Series Analysis (2015–2021)

The coronavirus disease 2019 (COVID-19)-pandemic-related overload of health systems has compromised the application of antimicrobial stewardship (AS) models and infection prevention and control (IPC) programs. We aimed to evaluate the impact of COVID-19 on antimicrobial consumption (AC) and antimicrobial resistance (AMR) in the University Hospital of Modena. A time series analysis with an autoregressive integrated moving average model was conducted from January 2015 to October 2021 to evaluate the AC in the whole hospital and the intensive care unit (ICU), the incidence density (ID) of bloodstream infections (BSIs) due to the main multidrug-resistant organisms, and of C. difficile infections (CDIs). After an initial peak during the COVID-19 period, a decrease in the trend of AC was observed, both at the hospital (CT: −1.104, p = 0.025) and ICU levels (CT: −4.47, p = 0.047), with no significant difference in the single classes. Among the Gram-negative isolates, we observed a significant increase only in the level of BSIs due to carbapenem-susceptible Pseudomonas aeruginosa (CL: 1.477, 95% CI 0.130 to 2.824, p = 0.032). Considering Gram-positive bacteria, an increase in the level of BSIs due to methicillin-resistant Staphylococcus aureus and in the trend of CDIs were observed, though they did not reach statistical significance (CL: 0.72, 95% CI −0.039 to 1.48, p = 0.062;CT: 1.43, 95% CI −0.002 to 2.863, p = 0.051;respectively). Our findings demonstrated that the increases in AMR and AC that appeared in the first COVID-19 wave may be later controlled by restoring IPC and AS programs to pre-epidemic levels. A coordinated healthcare effort is necessary to address the longer-term impact of COVID-19 on AC to avoid irreversible consequences on AMR.

Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections.

OBJECTIVES: To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options. METHODS: We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death. RESULTS: Seventeen patients treated for >72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58-73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3-10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression. CONCLUSIONS: Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF.

Herpes Simplex Virus Re-Activation in Patients with SARS-CoV-2 Pneumonia: A Prospective, Observational Study.

BACKGROUND: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care units were published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing HSV-1 PCR on plasma twice a week. METHODS: we conducted a prospective, observational, single-center study involving 70 consecutive patients with severe/critical SARS-CoV-2 pneumonia tested for HSV-1 hospitalized at Azienda Ospedaliero-Universitaria of Modena. RESULTS: of these 70 patients, 21 (30.0%) showed detectable viremia and 13 (62%) had clinically relevant manifestations of HSV-1 infection corresponding to 15 events (4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, one encephalitis and two hepatitis). HSV-1 positive patients were more frequently treated with steroids than HSV-1 negative patients (76.2% vs. 49.0%, p = 0.036) and more often underwent mechanical ventilation (IMV) (57.1% vs. 22.4%, p = 0.005). In the unadjusted logistic regression analysis, steroid treatment, IMV, and higher LDH were significantly associated with an increased risk of HSV1 re-activation (odds ratio 3.33, 4.61, and 16.9, respectively). The association with the use of steroids was even stronger after controlling for previous use of both tocilizumab and IMV (OR = 5.13, 95% CI:1.36-19.32, p = 0.016). The effect size was larger when restricting to participants who were treated with high doses of steroids while there was no evidence to support an association with the use of tocilizumab Conclusions: our study shows a high incidence of HSV-1 re-activation both virologically and clinically in patients with SARS-CoV-2 severe pneumonia, especially in those treated with steroids.

Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection.

SARS-CoV-2 infection can affect all human beings, including pregnant women. Thus, understanding the immunological changes induced by the virus during pregnancy is nowadays of pivotal importance. Here, using peripheral blood from 14 pregnant women with asymptomatic or mild SARS-CoV-2 infection, we investigate cell proliferation and cytokine production, measure plasma levels of 62 cytokines, and perform a 38-parameter mass cytometry analysis. Our results show an increase in low density neutrophils but no lymphopenia or gross alterations of white blood cells, which display normal levels of differentiation, activation or exhaustion markers and show well preserved functionality. Meanwhile, the plasma levels of anti-inflammatory cytokines such as interleukin (IL)-1RA, IL-10 and IL-19 are increased, those of IL-17, PD-L1 and D-dimer are decreased, but IL-6 and other inflammatory molecules remain unchanged. Our profiling of antiviral immune responses may thus help develop therapeutic strategies to avoid virus-induced damages during pregnancy.

The Impact of COVID-19 on UNAIDS 90-90-90 Targets: Calls for New HIV Care Models.

We compared 90-90-90 targets in 2020, during the coronavirus disease 2019 (COVID-19) pandemic, with the targets across the period 2017-2019 in people with HIV. We observed a significant loss in the 90-90-90 objectives in 2020 when compared with 2017-2019 that might be attributable to the COVID-19 crisis.

Accuracy of the serological detection of IgG and IgM to SARS-Cov-2: a prospective, cross-sectional study.

In response to the rapidly evolving of SARS-CoV-2 infection, numerous serological tests have been developed but their sensitivity and specificity are unclear. We collected serum samples of patients and health-care professionals to assess the accuracy of chemiluminescent (CLIA) and two lateral flow immunochromatographic assays (LFIA) to determine IgG and IgM antibodies to SARS-CoV-2 virus. We calculated the φ correlation for qualitative results and test accuracy, adopting the following case definition: either real-time-PCR positivity or serological positivity with at least two different tests. We analyzed 259 samples, obtaining strong correlation between CLIA and both LFIA for IgG (φ=0.9), and moderate correlation for IgM (φ=0.6). For patients, the sensitivity was suboptimal for all methods (CLIA 81%, LFIA A 85%, LFIA B 78%), while it was poor in asymptomatic health-care workers (CLIA 50%, LFIA A 50%, LFIA B 33%). Overall, CLIA is more sensitive and specific for the determination of both IgG and IgM, whilst both LFIA methods reported good sensitivity and specificity for IgG, but scarce sensitivity for the IgM determination. The determination of SARS-CoV-2-specific IgG is useful to detect infection 6 days from symptom onset.

Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia-Challenges, strengths, and opportunities in a global health emergency.

AIMS: The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia. METHODS: This was an observational prospective study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients' medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO2/FiO2 ratio <150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome. RESULTS: A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth "boosted mixed model" included 20 variables was selected from the model 3, achieved the best predictive performance (AUC = 0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example. CONCLUSION: This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.

Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia.

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM- plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.

Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia.

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.